Features and Outcomes of Methamphetamine-associated Pulmonary Arterial Hypertension.

RATIONALE: Although amphetamines are recognized as "likely" agents to cause drug- and toxin-associated pulmonary arterial hypertension (PAH), (meth)amphetamine-associated PAH (Meth-APAH) has not been well described. OBJECTIVES: To prospectively characterize the clinical presentation, histopathology, and outcomes of Meth-APAH compared with those of idiopathic PAH (iPAH). METHODS: We performed a prospective cohort study of patients with Meth-APAH and iPAH presenting to the Stanford University Pulmonary Hypertension Program between 2003 and 2015. Clinical, pulmonary angiography, histopathology, and outcomes data were compared. We used data from the Healthcare Cost and Utilization Project to estimate the epidemiology of PAH in (meth)amphetamine users hospitalized in California. MEASUREMENTS AND MAIN RESULTS: The study sample included 90 patients with Meth-APAH and 97 patients with iPAH. Patients with Meth-APAH were less likely to be female, but similar in age, body mass index, and 6-minute-walk distance to patients with iPAH. Patients with Meth-APAH reported more advanced heart failure symptoms, had significantly higher right atrial pressure (12.7 ± 6.8 vs. 9.8 ± 5.1 mm Hg; P = 0.001), and had lower stroke volume index (22.2 ± 7.1 vs. 25.5 ± 8.7 ml/m2; P = 0.01). Event-free survival in Meth-APAH was 64.2%, 47.2%, and 25% at 2.5, 5, and 10 years, respectively, representing more than double the risk of clinical worsening or death compared with iPAH (hazard ratio, 2.04; 95% confidence interval, 1.28-3.25; P = 0.003) independent of confounders. California data demonstrated a 2.6-fold increase in risk of PAH diagnosis in hospitalized (meth)amphetamine users. CONCLUSIONS: Meth-APAH is a severe and progressive form of PAH with poor outcomes. Future studies should focus on mechanisms of disease and potential therapeutic considerations.

Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria.

BACKGROUND: Many patients with chronic idiopathic urticaria (also called chronic spontaneous urticaria) do not have a response to therapy with H-antihistamines, even at high doses. In phase 2 trials, omalizumab, an anti-IgE monoclonal antibody [corrected] that targets IgE and affects mast-cell and basophil function, has shown efficacy in such patients. METHODS: In this phase 3, multicenter, randomized, double-blind study, we evaluated the efficacy and safety of omalizumab in patients with moderate-to-severe chronic idiopathic urticaria who remained symptomatic despite H-antihistamine therapy (licensed doses). We randomly assigned 323 patients to receive three subcutaneous injections, spaced 4 weeks apart, of omalizumab at doses of 75 mg, 150 mg, or 300 mg or placebo, followed by a 16-week observation period. The primary efficacy outcome was the change from baseline in a weekly itch-severity score (ranging from 0 to 21, with higher scores indicating more severe itching). RESULTS: The baseline weekly itch-severity score was approximately 14 in all four study groups. At week 12, the mean (±SD) change from baseline in the weekly itch-severity score was -5.1±5.6 in the placebo group, -5.9±6.5 in the 75-mg group (P=0.46), -8.1±6.4 in the 150-mg group (P=0.001), and -9.8±6.0 in the 300-mg group (P<0.001). Most prespecified secondary outcomes at week 12 showed similar dose-dependent effects. The frequency of adverse events was similar across groups. The frequency of serious adverse events was low, although the rate was higher in the 300-mg group (6%) than in the placebo group (3%) or in either the 75-mg or 150-mg group (1% for each). CONCLUSIONS: Omalizumab diminished clinical symptoms and signs of chronic idiopathic urticaria in patients who had remained symptomatic despite the use of approved doses of H-antihistamines. (Funded by Genentech and Novartis Pharma; ClinicalTrials.gov number, NCT01292473.).

Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies.

INTRODUCTION: In a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity. METHODS: LUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies. RESULTS: The median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose-response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed. CONCLUSIONS: These data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment. TRIAL REGISTRATION NUMBERS: The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov.

Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report.

The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI.

Incidence, correlates, and consequences of acute kidney injury in patients with pulmonary arterial hypertension hospitalized with acute right-side heart failure.

BACKGROUND: Though much is known about the prognostic influence of acute kidney injury (AKI) in left-side heart failure, much less is known about AKI in patients with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We identified consecutive patients with PAH who were hospitalized at Stanford Hospital for acute right-side heart failure. AKI was diagnosed according to the criteria of the Acute Kidney Injury Network. From June 1999 to June 2009, 105 patients with PAH were hospitalized for acute right-side heart failure (184 hospitalizations). AKI occurred in 43 hospitalizations (23%) in 34 patients (32%). The odds of developing AKI were higher among patients with chronic kidney disease (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.8-8.5), high central venous pressure (OR 1.8, 95% CI 1.1-2.4, per 5 mm Hg), and tachycardia on admission (OR 4.3, 95% CI 2.1-8.8). AKI was strongly associated with 30-day mortality after acute right-side heart failure hospitalization (OR 5.3, 95% CI 2.2-13.2). CONCLUSIONS: AKI is relatively common in patients with PAH and associated with a short-term risk of death.

ERG evaluation of daily, high-dose sildenafil usage.

PURPOSE: Sildenafil can cause transient, mild ERG changes in healthy individuals taking large single doses. Although the drug was originally intended for intermittent use in erectile dysfunction, it has now been approved for chronic use in subjects with pulmonary arterial hypertension (PAH). The purpose of our study is to investigate possible ERG changes in subjects using large doses of sildenafil on a chronic daily basis. METHODS: We examined five subjects with PAH taking sildenafil daily for 1-4 years. Full-field electroretinogram (ERG), multifocal ERG (mfERG), and color testing were performed. Three of the subjects returned on a later date for challenge off and on the medication. RESULTS: On chronic daily sildenafil, color vision testing was normal, and ERG and mfERG amplitudes were normal; however, cone implicit times on drug were modestly lengthened. There were no consistent full-field ERG changes when off the drug, but the mfERG showed a small amplitude increase and implicit time decrease, which returned 1 h after re-dosing. CONCLUSION: There was a modest lengthening of cone implicit time on chronic daily doses of sildenafil and a hint that some of these changes may be reversible in the short term. It does not appear that chronic sildenafil usage at these dosage levels is seriously toxic or threatening to vision.

Increased mortality in African Americans with idiopathic pulmonary arterial hypertension.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disorder that usually culminates in right ventricular failure and death without treatment. OBJECTIVE: To assess mortality trends by race and gender for idiopathic pulmonary arterial hypertension in the United States from 1994-1998. METHODS: The U.S. National Center for Health Statistics data for the years 1994-1998 was reviewed for deaths in which the underlying cause was primary pulmonary hypertension (ICD-9 code 416.0), now known as IPAH. The age, gender, race and state of residence of the deceased were abstracted from the Centers for Disease Control Wonder System (http://wonder.cdc.gov). Average annual age-adjusted region-, race- and gender-specific rates were then calculated. RESULTS: African-American women demonstrated the highest mortality rates for IPAH across all age groups compared to other racial and gender groups. No geographical differences in mortality rates were noted. An increase in mortality rates with advancing age was observed in all racial and gender groups, with the highest mortality rates for IPAH noted in the elderly. DISCUSSION: African Americans with IPAH exhibit a substantially increased mortality compared with Caucasians, particularly African-American women.

Current therapies for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature, characterized by relentless deterioration and death. Patients with PAH are known to be at increased risk for anesthetic complications and surgical morbidity and mortality. However, outcomes in patients have improved with the recent development of new drug therapies. The 3 major drug classes for treatment of PAH are prostanoids, endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors. In this review, the authors provide an overview of each drug class, its mechanism of action, indications, and current supportive literature. Surgical and interventional treatments of PAH, including atrial septostomy, pulmonary thromboendarterectomy, and transplantation, are briefly reviewed, and the rationale, indications, and selection criteria for each are discussed. Although available medical and surgical therapies for PAH have improved patient outcomes, acute decompensated right heart failure (RHF) remains a common and challenging complication of PAH. The authors review this topic and provide an outline of the general pathophysiology of RHF and an approach to its management.

Drug Development and Biologics in Asthma. A New Era.

Considerable progress has been made toward developing targeted biological therapeutics for asthma, due in large part to a deeper understanding of asthma pathophysiology. This explosion of knowledge has revealed asthma to be a much more complex and heterogeneous entity than previously understood. The identification of particular asthma phenotypes with distinct pathophysiologic mechanisms has opened up a new era for patient populations not well served by current therapies, especially patients with severe asthma.

Lung transplantation: a decade of experience.

BACKGROUND: Over the past 3 decades, the field of lung transplantation has been refined. However, many barriers exist that limit long-term success. The purpose of this study was to review a single institution's long-term experience with single and double lung transplantation and to assess the effect of different immunosuppressive therapies on outcomes. METHODS: Lung transplant recipients, both single and double, were reviewed, retrospectively. Patients were divided into five groups: group I, all lung transplants (n = 127); group II, single lung transplants (n = 73); group III, double lung transplants (n = 54); group IV, OKT3 induction therapy recipients (n = 27); and group V, RATG induction therapy recipients (n = 100). Rates of survival, rejection, bronchiolitis obliterans syndrome (BOS) and infection were analyzed at 1, 3, and 5 years. RESULTS: There were no significant differences in survival, acute rejection rate, freedom from BOS, nor infection between single and double lung transplant recipients. Induction therapy with RATG (group V) was associated with significantly improved survival and freedom from acute rejection, BOS, and infection when compared to OKT3 induction therapy (group IV). CONCLUSIONS: An earlier impression that RATG is superior to OKT3 induction therapy has borne true in terms of overall survival and incidence of BOS, acute rejection and infection rates. Lung transplantation, using RATG induction therapy, remains an important modality for end-stage pulmonary disease.

Health-related quality of life in patients with pulmonary arterial hypertension.

STUDY OBJECTIVES: Patients with pulmonary arterial hypertension (PAH) often present with dyspnea and severe functional limitations, but their health-related quality of life (HRQOL) has not been studied extensively. This study describes HRQOL in a cohort of patients with PAH. DESIGN: Cross-sectional study. SETTING: A tertiary care, university hospital-based, pulmonary hypertension (PH) clinic. PARTICIPANTS: We studied HRQOL in 53 patients with PAH (mean age, 47 years; median duration of disease, 559 days). Eighty-three percent were women, 53% received epoprostenol, and 72% reported moderate-to-severe functional limitations with a New York Heart Association class 3 or 4 at enrollment. MEASUREMENTS AND RESULTS: We examined HRQOL by administering the Nottingham Health Profile, Congestive Heart Failure Questionnaire, and Hospital Anxiety and Depression Scale. We used the Visual Analog Scale and standard gamble (SG) techniques to measure preferences for current health (utilities). Compared with population norms, participants reported moderate-to-severe impairment in multiple domains of HRQOL, including physical mobility, emotional reaction, pain, energy, sleep, and social isolation. Mean SG utilities were 0.71, suggesting that, on average, participants were willing to accept a 29% risk of death in order to be cured of PH. CONCLUSIONS: PAH is a devastating condition that affects predominately young women in the prime of their life. Understanding HRQOL and preferences are important in the care and management of these patients. Compared with population norms, patients with PAH have substantial functional and emotional limitations that adversely affect their HRQOL.

Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

While considerable advances have been achieved in the medical treatment of pulmonary arterial hypertension (PAH) over the past decade, surgical and interventional approaches continue to have important roles in those patients for whom medical therapy is unavailable or has been unsuccessful. These techniques include pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension, thoracic transplantation, and atrial septostomy. This chapter will provide evidence-based recommendations for the selection and timing of surgical and interventional treatments of PAH for physicians involved in the care of these complex patients.

High prevalence of autoimmune thyroid disease in pulmonary arterial hypertension.

STUDY OBJECTIVES: An association between thyroid disease and pulmonary arterial hypertension (PAH) has been reported, yet the pathogenetic relationship between these conditions remains unclear. Because immune system dysfunction may underlie this association, we sought to determine the prevalence of autoimmune thyroid disease (AITD) in patients with PAH. DESIGN AND SETTING: Prospective observational study at a single academic institution. PATIENTS: Sixty-three consecutive adults with PAH (ie, sustained pulmonary artery systolic pressure, > 25 mm Hg) were evaluated for clinical, biochemical, and serologic features of AITD. MEASUREMENTS: Thyroid gland dysfunction was determined by clinical examination for goiter, and by biochemical measurements of thyrotropin and free thyroxine. Immune system dysfunction was determined by serologic measurements of antibodies to thyroglobulin and thyroid peroxidase. First-degree family history of AITD also was ascertained in order to investigate for genetic clustering of autoimmunity. RESULTS: Thirty-one patients (49%; 95% confidence interval [CI], 37 to 62%) received diagnoses of AITD. Eighteen patients were newly diagnosed, and 9 patients required the initiation of pharmacologic treatment. There was no chronologic relationship between the diagnosis or treatment of PAH and that of AITD. Sixteen patients (25%; 95% CI, 15 to 36%) had 24 first-degree family members with AITD. CONCLUSIONS: Approximately half of the patients with PAH have concomitant AITD. These two conditions may be linked by a common immunogenetic susceptibility, and the elucidation of this association may advance the understanding of the pathophysiology and treatment of PAH. Systematic surveillance for occult thyroid dysfunction in patients with PAH may prevent the hemodynamic exacerbation of right heart failure.

Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

Although idiopathic pulmonary arterial hypertension is perceived as a progressive disease with a uniformly poor outcome, the natural history of disease is heterogeneous, with some patients dying within months of diagnosis and others living for decades. The course of the disease has also been altered by advances in medical therapies. The outcome of patients with other types of pulmonary arterial hypertension (PAH) has been less well characterized. Assessment of prognosis of such patients is important, as it influences both medical therapy and referral for transplantation. This chapter will provide evidence based recommendations to assess the prognosis of patients with PAH.

Weight gain after lung transplantation.

BACKGROUND: Weight gain is frequently observed after lung transplantation, but the magnitude, predictors and implications of weight gain after lung transplant are unknown. METHODS: This retrospective cohort study included 826 lung transplant recipients randomly selected from 12 international transplant centers. We included adult patients with available weight data at baseline and 1 year post-transplant. We examined demographic and clinical predictors of first year weight gain using a multiple linear regression model (n = 579) with percent weight change as the dependent variable. To study the association between first year weight gain and subsequent survival, we performed a Cox proportional hazards analysis. p < 0.05 was considered statistically significant. RESULTS: The median weight change was 10% (range -32% to 84%). On multi-variate analysis, increasing age and prolonged mechanical ventilation were inversely associated with weight gain; obstructive disease, interstitial disease and increasing ischemic time were positively associated with weight gain. Increasing baseline weight was negatively associated with weight gain in patients with obstructive and interstitial disease. The model accounted for 14% of the variance in weight gain. Patients with weight gain above the median had better subsequent survival (adjusted hazard ratio 0.61, 95% confidence interval 0.41 to 0.90). Infection was a more common cause of death in these patients, whereas malignant deaths were more frequent in patients with below-median weight gain. CONCLUSIONS: Substantial weight gain occurs in the first year after lung transplantation. The predictors of weight gain may be used to target high-risk patients for early intervention. Higher weight gain is associated with better subsequent survival.

PG490-88, a derivative of triptolide, attenuates obliterative airway disease in a mouse heterotopic tracheal allograft model.

The current treatment of obliterative bronchiolitis in lung transplant recipients is sub-optimal. Triptolide is a novel immunosuppressant that has a mechanism of action distinct from currently available immunosuppressants, including induction of T-cell apoptosis, blockade of fibroblast proliferation/maturation and inhibition of transforming growth factor-beta (TGF-beta) mRNA production. We hypothesized that triptolide may be helpful in blocking obliterative airway disease in lung transplant recipients. We investigated the effect of PG490-88, a water-soluble derivative of triptolide, in a mouse heterotopic tracheal allograft model of obliterative airway disease. We show that PG490-88 attenuates airway obliteration in this model and inhibits accumulation of inflammatory cells, and therefore may have preventive or therapeutic benefits for patients with obliterative airway disease (OAD) following lung transplantation.

Characteristics and outcome after hospitalization for acute right heart failure in patients with pulmonary arterial hypertension.

BACKGROUND: Although much is known about the risk factors for poor outcome in patients hospitalized with acute heart failure and left ventricular dysfunction, much less is known about the syndrome of acute heart failure primarily affecting the right ventricle (acute right heart failure). METHODS AND RESULTS: By using Stanford Hospital's pulmonary hypertension database, we identified consecutive acute right heart failure hospitalizations in patients with PAH. We used longitudinal regression analysis with the generalized estimating equations method to identify factors associated with an increased likelihood of 90-day mortality or urgent transplantation. From June 1999 to September 2009, 119 patients with PAH were hospitalized for acute right heart failure (207 episodes). Death or urgent transplantation occurred in 34 patients by 90 days of admission. Multivariable analysis identified a higher respiratory rate on admission (>20 breaths per minute; OR, 3.4; 95% CI, 1.5-7.8), renal dysfunction on admission (glomerular filtration rate <45 mL/min per 1.73 m2; OR, 2.7; 95% CI, 1.2-6.3), hyponatremia (serum sodium ≤136 mEq/L; OR, 3.6; 95% CI, 1.7-7.9), and tricuspid regurgitation severity (OR, 2.5 per grade; 95% CI, 1.2-5.5) as independent factors associated with an increased likelihood of death or urgent transplantation. CONCLUSIONS: These results highlight the high mortality after hospitalizations for acute right heart failure in patients with PAH. Factors identifiable within hours of hospitalization may help predict the likelihood of death or the need for urgent transplantation in patients with PAH.

A novel non-invasive method of estimating pulmonary vascular resistance in patients with pulmonary arterial hypertension.

BACKGROUND: The assessment of pulmonary vascular resistance (PVR) plays an important role in the diagnosis and management of pulmonary arterial hypertension (PAH). The main objective of this study was to determine whether the noninvasive index of systolic pulmonary arterial pressure (SPAP) to heart rate (HR) times the right ventricular outflow tract time-velocity integral (TVI(RVOT)) (SPAP/[HR x TVI(RVOT)]) provides clinically useful estimations of PVR in PAH. METHODS: Doppler echocardiography and right-heart catheterization were performed in 51 consecutive patients with established PAH. The ratio of SPAP/(HR x TVI(RVOT)) was then correlated with invasive indexed PVR (PVRI) using regression and Bland-Altman analysis. Using receiver operating characteristic curve analysis, a cutoff value for the Doppler equation was generated to identify patients with PVRI > or = 15 Wood units (WU)/m2. RESULTS: The mean pulmonary arterial pressure was 52 +/- 15 mm Hg, the mean cardiac index was 2.2 +/- 0.6 L/min/m2, and the mean PVRI was 20.5 +/- 9.6 WU/m2. The ratio of SPAP/(HR x TVI(RVOT)) correlated very well with invasive PVRI measurements (r = 0.860; 95% confidence interval, 0.759-0.920). A cutoff value of 0.076 provided well-balanced sensitivity (86%) and specificity (82%) to determine PVRI > 15 WU/m2. A cutoff value of 0.057 increased sensitivity to 97% and decreased specificity to 65%. CONCLUSION: The novel index of SPAP/(HR x TVI(RVOT)) provides useful estimations of PVRI in patients with PAH.

Health-related quality of life and patient-reported outcomes in pulmonary arterial hypertension.

Advances in our understanding of the basic pathophysiology of pulmonary arterial hypertension (PAH) has led to an expanding number of therapeutic options. The ultimate goals of therapy are to lengthen survival while improving symptoms and quality of life. A wealth of research in other conditions has established health-related quality of life (HRQoL) to be an important clinical endpoint. Until recently, however, little was known about HRQoL in PAH, and how best to measure it. Over the past few years, several studies have begun contributing to this growing area of research. Instruments used to assess HRQoL have varied between studies. The extent to which these instruments are valid in PAH depend on their specific measurement properties. In this article, we provide an overview of the different types of patient-reported outcomes (PROs) used in PAH, focusing in particular on the measurement of HRQoL. In the process, we review the current literature on HRQoL in PAH, summarize the available data from randomized controlled trials, and discuss the implications of these findings on future research. Despite significant progress, the study of HRQoL in PAH remains a nascent field relative to other conditions. As the use of PROs continues to increase, additional work will be needed to begin standardizing the reporting and interpretation of such outcomes in future clinical trials.